Plasmodium falciparum is a major cause of death in the world today. Toll-like receptors (TLRs) are the primary means the innate immune system uses to recognize and destroy invading microbes, including parasites. Paradoxically, TLRs also cause the inflammation and cytokinemia that kills infected people. We hypothesize that TLRs are central mediators of the pathogeneais of Plasmodium falciparum malaria. Animal studies have established a role for TLRs in malaria, but have failed to define the precise TLR(s) involved. In some individuals, malaria acquisition results in asymptomatic disease, indicative of a nearly total failure of TLRs. This failure probably accounts for the existence of well-documented populations of infected individuals with asymptomatic (or minimally symptomatic) parasitemia. Such individuals are an importanl reservoir for P falciparum. Our long term goal is the development an affordable therapeutic vaccine that can eradicate malaria from asymptomatic (or minimally symptomatic) parasitemic individuals. Furthermore, such a vaccine has the potential to be an important component of a preventative malaria vaccine as a potent adjuvant. In this application, we propose to define "normal innate immune defenses" to malaria by determining which TLRs and TIR-domain containing adapter proteins provide resistance to infection. We will use a variety of approaches including in vivo work in TLR knockout animals and in vitro work with heterologously transfected cell lines that we have developed. In addition, we will determine the involvement of TLRs in malaria patients from the Amazon region of Brazil by examining gene expression profiles in highly purified monocytes. Monocytes will be studied functionally for their responses to TLR ligands. Patients will be restudied after a curative chemotherapeutic regimen of anti malarial drugs. Data derived from these studies should indicate which TLRs are involved in malaria pathogenesis, and if the development of the asymptomatic parasitemic state is due to a failure of TLRs to become fully activated.